1qdu

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spinqualitylabelsall models 1qdu, resolution 2.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR ZEVD-DCBMK

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

BACKGROUND: In the initial stages of Fas-mediated apoptosis the cysteine, protease caspase-8 is recruited to the cell receptor as a zymogen, (procaspase-8) and is incorporated into the death-signalling complex., Procaspase-8 is subsequently activated leading to a cascade of proteolytic, events, one of them being the activation of caspase-3, and ultimately, resulting in cell destruction. Variations in the substrate specificity of, different caspases have been reported. RESULTS: We report here the crystal, structure of a complex of the activated human caspase-8 (proteolytic, domain) with the irreversible peptidic inhibitor, Z-Glu-Val-Asp-dichloromethylketone at 2.8 A resolution. This is the first, structure of a representative of the long prodomain initiator caspases and, of the group III substrate specificity class. The overall protein, architecture resembles the caspase-1 and caspase-3 folds, but shows, distinct structural differences in regions forming the active site. In, particular, differences observed in subsites S(3), S(4) and the loops, involved in inhibitor interactions explain the preference of caspase-8 for, substrates with the sequence (Leu/Val)-Glu-X-Asp. CONCLUSIONS: The, structural differences could be correlated with the observed substrate, specificities of caspase-1, caspase-3 and caspase-8, as determined from, kinetic experiments. This information will help us to understand the role, of the various caspases in the propagation of the apoptotic signal. The, information gained from this investigation should be useful for the design, of specific inhibitors.

Disease

Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[601763], Breast cancer, protection against OMIM:[601763], Hepatocellular carcinoma, somatic OMIM:[601763]

About this Structure

1QDU is a Single protein structure of sequence from Homo sapiens with PHQ as ligand. Full crystallographic information is available from OCA.

Reference

The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis., Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grutter MG, Structure. 1999 Sep 15;7(9):1125-33. PMID:10508784

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